3-Benzoylfluoro-methanesulfonanilides

ABSTRACT

Benzoylhaloalkanesulfonanilides of the general type ##SPC1## 
     Wherein R x  is a haloalkyl group having up to four carbon atoms and at least one halogen atom bonded to the alpha carbon atom or if there is no halogen bonded to said alpha carbon atom, having at least 2 halogen atoms bonded to the beta carbon atom, R is hydrogen, alkyl or alkenyl containing not more than three carbon atoms, or a pharmaceutically acceptable cation; each Y .Iadd.and Y&#39; .Iaddend.is selected from hydroxy, halogen and alkyl, alkoxy, haloalkyl and haloalkoxy groups having up to 4 carbon atoms and n and n&#39;  are each 0-3. These compounds and their salts have valuable pharmacological activity as anti-inflammatory agents. .Iadd.

CROSS-REFERENCES TO RELATED APPLICATIONS .Iaddend.

.[.This application is a continuation-in-part of the copendingapplication Ser. No. 588,338, filed Oct. 21, 1966 and now abandoned, andSer. No. 719,741, filed Apr. 8, 1968. .Iadd.

Application Ser. No. 832,824 was a continuation-in-part of theapplications Ser. No. 588,338 filed Oct. 21, 1966 and now abandoned andSer. No. 719,741 filed Apr. 8, 1968 and now abandoned. .Iaddend.

BACKGROUND OF THE INVENTION

The invention relates to .Iadd.certain .Iaddend.haloalkanesulfonanilides.Iadd.(specifically certain haloalkylsulfonamidobenzophenones).Iaddend.which have valuable pharmacological activity.Iadd., especiallyanti-inflammatory activity.Iaddend.. Steroids having cortisone-likeactivity have heretofore been used for treatment of inflammatory, e.g.arthritic conditions. While these are effective, they have certainundesirable side effects. Consequently, there is a need for effectiveanti-inflammatory agents which are free of such disadvantages.

The novel and efficacious compounds of the present invention arenon-steroidal in character, and their use does not entail side effectspeculiar to steroid therapy. Of particular value in theanti-inflammatory compounds of the present invention is their relativelylow toxicity, and they are well-tolerated by the gastrointestinal tract.A number of the new compounds also have anti-pyretic and analgesicactivity. The pharmacological activities of these compounds have beenelucidated by means of mammalian animal tests. .Iadd.

The prior art also includes disclosures of certainhaloalkanesulfonanilides, alleged to have protective action against theattack of textile pests, mold and bacteria. Representative of thesedisclosures are those contained in British Patents 738,758 and 856,452and French Patent 1,188,591.

Thus, British Patent 738,758 discloses the formula

    [hal.sub.x --R.sub.1.SO.sub.2.NH].sub.n --R

wherein R is said to include mono- or divalent polynuclear carbocyclicradicals wherein aromatic nuclei are linked either directly by a C--C--linkage or by the bridging members --O--, --S--, --SO₂ --, --SO--, --CH₂--, --CH=CH--, -- CO--, --N=N--, or they are condensed, R₁ is analiphatic hydrocarbon radical, x is an integer and n is 1 or 2 dependingupon the valency of R. This is the only disclosure in the British Patentof any structure in which aromatic nuclei are linked by the bridgingmember --CO--, although theoretical lists of intermediates in thepreparation of compounds containing other linking groups betweenaromatic rings are named as are compounds having structures in which tworings are bonded directly or are fused, or are connected through oxy,sulfonyl and azo groups.

British Patent 856,452 relates (inter alia) to haloalkyl (e.g.dichloromethanesulfonyl, chloroethanesulfonyl, trifluoro- ortrichloromethanesulfonyl, trichloroethanesulfonyl-, etc.). Sulfonamidesof amidodiphenylamines which are halogenated on one or both aromaticnuclei. It also refers to British Patent 738,758 and summarizes certainof its teachings.

French Patent 1,188,591 has a disclosure somewhat similar to that ofBritish Patent 738,758 but of comparable or less pertinence to thesubject matter of the present case.

Thus, the particular haloalkylsulfonamidobenzophenone anti-inflammatoryagents of the present invention are not rendered obvious by theteachings of these foreign patents, individually or collectively.

DESCRIPTION OF THE INVENTION .Iaddend.

The present invention contemplates providing a novel class ofpharmacologically active compounds, especially compounds withanti-inflammatory activity. The invention further aims to providecompositions of the novel, active compounds which are suitable foradministration for pharmacological purposes. Within the purview of theinvention are processes for the preparation and use of the compounds ofthe invention for pharmacological purposes. Still other objectives ofthe invention will become apparent to those skilled in the art fromreading the following disclosure.

The novel benzoylhaloalkanesulfonanilides of the invention (which mayalso be termed haloalkylsulfonamidobenzophenones) have the formula:

Formula I ##SPC2##

wherein R_(x) is a haloalkyl group having up to four carbon atoms and atleast one halogen atom bonded to the alpha carbon atom or if there is nohalogen bonded to said alpha carbon atom, having at least 2 halogenatoms bonded to the beta carbon atoms, R is hydrogen, alkyl or alkenylcontaining not more than three carbon atoms, or a pharmaceuticallyacceptable cation; each Y .Iadd.and Y' .Iaddend. is selected fromhydroxy, halogen and alkyl, alkoxy, haloalkyl and haloalkoxy groupshaving up to 4 carbon atoms and n and n' are each 0-3.

Unless otherwise specified, in the compounds of the invention, thevarious halogen atoms in an R_(x) group can be the same or different,the various Y .Iadd.and Y'.Iaddend. groups can be the same or different(regardless of whether they occur as substituents on the same ring or onthe two different rings) and n and n' can be the same or different. Whenn and n' are both zero, the rings will be unsubstituted, i.e. thecompounds will have the formulae: ##SPC3##

The compounds of Formula I have anti-inflammatory action when tested bystandard test methods using animals, as described more particularlyhereinafter.

Compounds of this invention wherein R_(x) contains up to two carbonatoms are presently preferred, and those in which R_(x) contains onecarbon atom are most preferred. Compounds wherein the halogen in theR_(x) is fluorine and/or chlorine are presently preferred, particularlywherein the halogen therein is all fluorine (especially compounds inwhich R_(x) is HCF₂ -- or H₂ CF--). The compounds in which R_(x) isperfluorinated also form a preferred group, particularlytrifluoromethyl.

Preferably in the foregoing groups and other compounds of the invention,the haloalkylsulfonamido group in the compounds of the invention isoriented meta to the carbonyl group.

The compounds in which n and n' are zero, or in which one of them iszero and the other is one and the Y or Y' is hydroxy have outstandinganti-inflammatory activity and therefore also form a preferred class.

When R is alkyl, it is preferred that R is methyl or ethyl. When Yand/or Y' are alkyl or alkoxy, it is preferred that the alkyl and alkoxygroups contain one carbon atom. Similarly when Y and/or Y' are haloalkylor haloalkoxy, it is preferred that they contain one carbon atom.

The products of the present invention are effective anti-inflammatoryagents and some also are analgesic and anti-pyretic agents. Theanti-inflammatory activity can be conveniently demonstrated using assaysdesigned to test the ability of these compounds to antagonize the localedema which is a characteristic of the anti-inflammatory response (ratfoot edema test) and to inhibit the onset of the erythematousmanifestation of inflammation (guinea pig erythema test).

The edema test is performed on adult female rats. One group of 10 ratsserves as non-medicated controls, while another group of 10 ratsreceives the test compound at various times prior to the induction ofthe edema, usually 15 minutes, one hour and/or 18 hours. The testcompound is administered as a suspension in 4 percent aqueous solutionof acacia. Edema is induced by the plantar injection of 0.5 percentcarrageenin (0.1 ml./foot) into the right hind foot. The left hind footreceives a like volume of 0.9 percent saline solution. One hour later,the volume of each hind foot is determined plethysmographically. Theedema is expressed as the increase in the volume of the edemogeninjected foot (volume of the "edemogen foot" less the volume of the"saline foot"). The percent inhibition is calculated by dividing themean increase in the edema of the edemogen foot of the medicated groupby the mean increase in the non-medicated group, multiplied by 100. Anactive dose is that giving a statistically significant inhibition of theinduced edema, usually about 30-35 percent inhibition.

Leading references to this method are:

(1) Adamkiewicz et al., Canad. J. Biochem. Physio. 33: 332, 1955;

(2) Selye, Brit. Med. J. 2: 1129, 1949; and

(3) Winter, Proc. Soc. Exper. Biol. Med. 111: 544, 1962.

The erythema test is performed on adult, albino guinea pigs of eithersex weighing 400-600 g. Hair is removed from the abdomen of the animalsby a depilatory mixture the afternoon of the day prior to the day onwhich they are to be used. One group of 5 animals serves asnon-medicated controls, while another group of 5 receives the testcompound 30 minutes prior to direct exposure to ultraviolet light. Forinduction of erythema, the animal is restrained on a small animal board.Three circular sections (6-8 mm. in diameter) of the ventrolateralabdominal area of the animal are then exposed to a controlled amount ofultraviolet radiation. Two hours after exposure, the erythema is scored0-5 on the basis of its intensity and completeness (full or partialcircles). The maximal score per animal is 15. The percent inhibition iscalculated on the basis of the mean score for the medicated group versusthe non-medicated group. An active dose is taken to be that giving astatistically significant inhibition of the induced erythema, usually35-40 percent inhibition. Modifications of this test include variationin the time and method of drug administration.

Leading references to this method are:

(1) Wilhelm, Schweiz, Med. Wschr. 25: 577, 1949, and

(2) Winder et al., Arch. Int. Pharmacodyn. 116: 261, 1958.

In the rat foot edema test and/or the guinea pig erythema test, thefollowing compounds have been found to be effective anti-inflammatoryagents (i.e., to have significant activity) at dosage levels of 100mg./kg. or less in single doses:

3-benzoyldifluoromethanesulfonanilide,

3-benzoyldifluoromethanesulfonanilide, sodium salt,

3-benzoyl-4-hydroxytrifluoromethanesulfonanilide,

3-benzoylfluoromethanesulfonanilide,

3-(4-chloro-2-methylbenzoyl)trifluoromethanesulfonanilide,

N-methyl-3-benzoyltrifluoromethanesulfonanilide,

N-ethyl-3-benzoyltrifluoromethanesulfonanilide,

3-(4-methylbenzoyl)fluoromethanesulfonanilide,

3-(4 -chlorobenzoyl)difluoromethanesulfonanilide,

3-benzoyl-2,2,2-trifluoroethanesulfonanilide,

3-(4-methoxybenzoyl)difluoromethanesulfonanilide,

3-(4-methoxybenzoyl)fluoromethanesulfonanilide,

4-benzoyldifluoromethanesulfonanilide,

3-(2-hydroxybenzoyl)trifluoromethanesulfonanilide,

3-benzoyltrifluoromethanesulfonanilide,

4-benzoyltrifluoromethanesulfonanilide,

3-(4-methylbenzoyl)trifluoromethanesulfonanilide,

3-(4-methoxybenzoyl)trifluoromethanesulfonanilide,

3-(4-chlorobenzoyl)trifluoromethanesulfonanilide,

3-(3-chlorobenzoyl)trifluoromethanesulfonanilide,

3-(2-chlorobenzoyl)trifluoromethanesulfonanilide,

3-(2-methylbenzoyl)trifluoromethanesulfonanilide,

3-benzoylperfluoroethanesulfonanilide,

3-(4-fluorobenzoyl)trifluoromethanesulfonanilide,

3-benzoyl-4-chlorotrifluoromethanesulfonanilide,

3-benzoyl-(2-hydroperfluoroethane)sulfonanilide,

3-benzoyl-4-chlorodifluoromethanesulfonanilide,

4-chloro-3-(4-chlorobenzoyl)trifluoromethanesulfonanilide,

4-chloro-3-(4-fluorobenzoyl)trifluoromethanesulfonanilide,

3-(4-fluorobenzoyl)difluoromethanesulfonanilide,

3-benzoylchloromethanesulfonanilide,

4-chloro-3-(4-fluorobenzoyl)difluoromethanesulfonanilide, and

4-chloro-3-(4-chlorobenzoyl)difluoromethanesulfonanilide.

Aspirin, which is very widely used as an anti-inflammatory agent, isonly marginally active at 150 mg./kg. in the rat foot edema test.

The compounds named hereinabove, and their salts are made by the generalprocess described hereinbelow and as further specifically illustrated inthe examples.

To produce the compounds of Formula I, wherein R is hydrogen, anaminobenzophenone is condensed with a haloalkylsulfonyl halide oranhydride according to the following scheme: ##SPC4##

wherein R_(x), n,n'.[.and Y.]. .Iadd.Y and Y' .Iaddend. are aspreviously defined and X represents a halogen atom, preferably chlorineor fluorine, or the corresponding anhydride grouping --OSO₂ R_(x) (R_(x)being defined as above). Approximately equivalent amounts of thereactants are brought together at temperatures most often rangingbetween about -15° and 150° C. If necessary or desirable, the reactioncan be carried out in a pressure vessel. The reaction is preferably, butnot necessarily, carried out in the presence of an acid acceptor such asthe alkali or alkaline earth metal carbonates and bicarbonates or atertiary amine such as pyridine, triethylamine or N,N-dimethylaniline.The amount of the acid acceptor can be varied widely; however, a 10 molepercent excess of that amount of base sufficient to bind the liberatedstrong acid (HX) is routinely employed.

The condensation is usually conducted in the presence of an appropriateinert organic solvent. Typical solvents suitable for this purpose aremethylene chloride, chloroform, carbon tetrachloride, benzene, toluene,bis(2-methoxyethyl) ether, acetonitrile, nitromethane, and the like.

After reaction is complete, if the reaction solvent is not watermiscible, the product mixture can be extracted with a dilute aqueousbase solution. The product, in the form of a salt which is usuallysoluble in the aqueous layer, is precipitated therefrom by addition of amineral acid such as hydrochloric or sulfuric acid, and collected byfiltration. Alternatively the product mixture can be washed with aqueoushydrochloric acid, the solvent evaporated in vacuo, and the residuedissolved in a dilute aqueous base solution which is washed withdichloromethane and treated with decolorizing charcoal. The product, inthe form of a salt is then isolated as described above.

If the reaction solvent is water miscible, the product is generallyobtained by dilution of the reaction mixture with water. The product, asolid or oil, is separated and purified by conventional methods. Thecompounds prepared according to the foregoing procedures are crystallinesolids purified, in general, by recrystallization from aqueous alcohol,trichloroethylene, hexane, benzene-hexane mixtures and the like. Elutionchromatography has also been found to be a useful purificationtechnique.

An additional and preferred method of obtaining the compounds of theinvention in which Y .Iadd.or Y' .Iaddend.is hydroxy is by cleavage ofthe alkoxy group of the comparable sulfonanilides in which Y .Iadd.or Y'.Iaddend.is alkoxy. This can be done conveniently with hydrogeniodide-acetic acid mixtures. Alternatively, other known ether cleavagemethods, e.g. hydrobromic acid-acetic acid, may be used.

When R is hydrogen in the compounds of the invention, this hydrogen isacidic in nature. Consequently, they readily form salts of alkalimetals, alkaline earth metals, amines and the like. Pharmaceuticallyacceptable salts of these acidic compounds are included within the scopeof Formula I, when R is a pharamaceutically acceptable cation.

Many of the salts are readily prepared by adding the stoichiometricamount of the selected base in inert solvent solution to the acidiccompound. The resulting solution is treated to remove the solvent, e.g.by evaporation under reduced pressure. The salts are conveniently usedin making pharmaceutical preparations for administration of thecompounds, e.g. in capsules for oral administration. Another method forthe preparation of salts of the invention is the reaction of a salt ofthe invention with an organic or inorganic salt in a cation exchangereaction.

Compounds of the invention wherein R is alkyl or alkenyl are readilyprepared by the reaction of the compounds of the invention where R ishydrogen or a cation with an alkyl or alkenyl halide. This method foralkylation is known to the art.

Suitable haloalkanesulfonylanhydrides and halides (e.g. chlorides andfluorides) for use as starting materials in these procedures are knownto the art, for example:

fluoromethanesulfonyl chloride,

fluorochloromethanesulfonyl chloride,

difluoromethanesulfonyl chloride,

dichloromethanesulfonyl chloride,

2,2,2-trifluoroethanesulfonyl chloride,

trifluoromethanesulfonyl chloride,

1,1,2,2-tetrafluoroethanesulfonyl chloride,

bromomethanesulfonyl chloride,

2,2,3,3-tetrafluoropropanesulfonyl chloride,

2-hydroperfluoropropanesulfonyl chloride,

and may others disclosed e.g. in U.S. Pat. No. 2,732,398.

The aminobenzophenones used in producing the compounds of the inventionare generally described in the chemical literature or can be preparedfrom corresponding known substituted nitrobenzophenones by reduction.Any nitrobenzophenones or aminobenzophenones not specifically disclosedin the chemical literature are prepared by methods known in theliterature for analogous compounds. Exemplary of such starting materialsare:

5-amino-2-chlorobenzophenone,

3-amino-4'-fluorobenzophenone,

3-amino-5-bromobenzophenone,

3-amino-4'-ethylbenzophenone,

3-amino-2'-ethoxybenzophenone,

3-amino-4'-ethoxybenzophenone, etc.

The following examples are given for the purpose of further illustratingthe present invention, but are not intended to limit the scope thereof.All melting and boiling points are uncorrected. All parts are by weightunless otherwise specified in the examples.

EXAMPLE 1 Preparation of 3-benzoylfluoromethanesulfonanilide

A 500 ml flask fitted with reflux condenser was charged with 8.7 g. ofN,N-dimethylaniline (0.72 mole), a solution of 12.8 g. of3-aminobenzophenone (0.065 mole) in 50 ml. of methylene chloride, 8.6 g.of fluoromethanesulfonyl chloride (0.065 mole, B.P. 138-141° C.) and 200ml. of methylene chloride. The mixture was heated at reflux temperatureovernight, then cooled, washed twice with 500 ml. portions of 10 percenthydrochloric acid and dried over anhydrous magnesium sulfate. Thesolvent was removed by evaporation leaving an oil that crystallizedafter 3 hours in the vacuum oven to afford relatively pure product, M.P.116-119° C. This solid was taken up in 300 ml. of 10 percent aqueoussodium hydroxide. The solution was warmed, treated with activated carbonand acidified to pH 1 with concentrated hydrochloric acid. An oil formedinitially but crystallized to give a solid, M.P. 115-117° C. This wasrecrystallized from 95 percent ethanol to give analytically pureproduct, M.P. 117-120° C.

Analysis.--Calculated for C₁₄ H₁₂ FNO₃ S (percent): C, 57.3; H, 4.1.Found (percent): C, 57.7; H, 4.1.

EXAMPLE 2 Preparation of 3-benzoyldifluoromethanesulfonanilide

A one liter flask fitted with reflux condenser was charged with 0.1 moleof 3-aminobenzophenone, 10 ml. of pyridine, 0.1 mole ofdifluoromethanesulfonyl chloride, and 400 ml. of benzene. The mixturewas heated at 50-55° C. for 72 hours and then extracted with 10 percentaqueous sodium hydroxide. Acidification of the alkaline layer produced asolid which was recrystallized from trichloroethylene-hexane mixtures toafford analytically pure product, M.P. 99-100.5° C.

Analysis.--Calculated for C₁₄ H₁₁ F₂ NO₃ S (percent): C, 54.1; H, 3.6;N, 4.4. Found (percent): C, 53.9; H, 3.6; N, 4.4.

EXAMPLES 3-32

By the use of the general procedure of Examples 1 and 2 and thesubstitution of other haloalkanesulfonyl chlorides and other substitutedaminobenzophenone starting materials, all of which are known, thefollowing exemplary compounds are obtained:

    __________________________________________________________________________                                  M.P., ° C.                               Ex.                           (uncor-                                         No.                           rected)                                         __________________________________________________________________________    3  2-benzoyldifluoromethanesulfonanilide                                                                    79.5-81                                         4  3-(4-methylbenzoyl)difluoromethanesulfonanilide                                                          119-121                                         5  3-(4-chlorobenzoyl)difluoromethanesulfonanilide                                                          127-129                                         6  3-(4-methoxybenzoyl)fluoromethanesulfonanilide                                                           116.5-118.5                                     7  3-benzoyl-4-chlorodifluoromethanesulfonanilide                                                           99-102                                          8  3-benzoyl-4-chlorofluoromethanesulfonanilide                                                             113-116                                         9  4-benzoyldifluoromethanesulfonanilide                                                                    124.5-126.5                                     10 2-benzoylfluoromethanesulfonanilide                                                                      74.5-75.5                                       11 3-(4-chlorobenzoyl)fluoromethanesulfonanilide                                                            118-120                                         12 3-(4-n-butoxybenzoyl)fluoromethanesulfonanilide                                                          113-117                                         13 3-(4-t-butylbenzoyl)fluoromethanesulfonanilide                                                           102-105                                         14 3-(4-fluorobenzoyl)difluoromethanesulfonanilide                                                          80-84                                           15 3-(4-fluorobenzoyl)fluoromethanesulfonanilide                                                            127-129.5                                       16 3-(4-hydroxybenzoyl)difluoromethanesulfonanilide.sup.(1)                                                 150-152                                         17 2-benzoyl-4-chlorodifluoromethanesulfonanilide                                                           98-100                                          18 2-benzoyl-4-chlorofluoromethanesulfonanilde                                                              88-89.5                                         19 3-benzoyl-(2-hydroperfluoroethane)sulfonanilide                                                          80-80.5                                         20 3-benzoyl-(2-hydroperfluoro-n-propane)sulfonanilide                                                      94-96                                           21 3-benzoylchloromethanesulfonanilide                                                                      95-97                                           22 4-chloro-3-(4-fluorobenzoyl)difluoromethane-                                                             101-103                                            sulfonanilide.                                                             23 4-chloro-3-(4-methylbenzoyl)difluoromethane-                                                             77-79                                              sulfonanilide.                                                             24 4-chloro-3-(4-chlorobenzoyl)difluoromethane-                                                             81-83                                              sulfonanilide.                                                             25 3-benzoyl-4-chlorochloromethanesulfonanilide                                                             130-133                                         26 3-(4-methylbenzoyl)chloromethanesulfonanilide                                                            118-119                                         27 3-(2-methylbenzoyl)chloromethanesulfonanilide                                                            88-89                                           28 3-(2-methylbenzoyl)fluoromethanesulfonanilide                                                            101-102                                         29 3-(2-chlorobenzoyl)chloromethanesulfonanilide                                                            99-101                                          30 3-(2-chlorobenzoyl)fluoromethanesulfonanilide                                                            123-125                                         31 3-(4-chlorobenzoyl)chloromethanesulfonanilide                                                            149-150                                         32 3-benzoylperfluoro-n-butanesulfonanilide                                                                 .sup.(2)                                        __________________________________________________________________________     .sup.(1) Prepared by the method of Example 84 from the compound of Exampl     34.                                                                           .sup.(2) B.P. 186° C./0.09 mm.                                    

EXAMPLE 33 Preparaton of the sodium salt of3-benzoyldifluoromethanesulfonanilide

To a solution of 12.21 g. of reagent grade sodium hydroxide (0.305 mole)in 300 ml. of water were added 95 g. of3-benzoyldifluoromethanesulfonanilide (0.305 mole). The mixture wasstirred until dissolution was complete and the solution had pH 7.2(sensitive pH paper). Water was removed to give a yellow solid which wastaken up in about 200 ml. of glyme and treated with activated charcoal.The clear solution was then added dropwise with vigorous stirring to 5liters of ethyl ether. The crystalline salt was isolated by filtration,washed with 4 liters of ethyl ether and dried to give analytically pureproduct, M.P. (dec.) 235° C.

Analysis.--Calculated for C₁₄ H₁₀ F₂ NaNO₃ S (percent): C, 50.45; H,3.05. Found: (percent): C, 50.6; H, 3.2.

Other salts are made by the same process, substituting other alkali oralkaline earth metal hydroxides for sodium hydroxide. Amine salts aremade using alcohol solutions of the stoichiometric amount of the amine,in a similar manner, e.g. the dimethylaminoethanol salt. Alternatively,water solutions of the amine may be used.

EXAMPLE 34 Preparation of3-(4-methoxybenzoyl)difluoromethanesulfonanilide

A one liter flask fitted with reflux condenser was charged with 56.8 g.of 3-amino-4'-methoxybenzophenone (0.25 mole), 26.5 g. ofN,N-dimethylaniline (0.30 mole), 37.8 g. of difluoromethanesulfonylchloride (0.25 mole) and 350 ml. of methylene chloride. The mixture washeated at reflux temperature for 36 hours and then was extracted withdilute aqueous sodium hydroxide. After treatment with charcoal,acidification of the alkaline extract afforded a solid which was washedwith hot heptane and recrystallized from carbon tetrachloridehexanemixtures to afford analytically pure product, M.P. 118-120° C.

Analysis.--Calculated for C₁₅ H₁₃ F₂ NO₄ S (percent): C, 52.8; H, 3.9;N, 4.1. Found (percent): C, 52.6; H, 3.9; N, 4.2.

EXAMPLE 35 Preparation of 3-benzoyl-2,2,2-trifluoromethanesulfonanilide

A one liter flask was charged with 29.6 g. of 3-aminobenzophenone (0.15mole), 9.2 g. of 2,2,2-trifluoroethanesulfonyl chloride (0.05 mole) and250 ml. of methylene chloride. The mixture was allowed to stand forabout an hour with occasional shaking. The reaction mixture was thenwashed with dilute hydrochloric acid to remove excess3-aminobenzophenone, and the solvent was removed by evaporation toafford a solid product. Recrystallization of the solid fromtrichloroethylene and drying gave analytically pure product, M.P.105.5-107° C.

Analysis.--Calculated for C₁₅ H₁₂ F₃ NO₃ S (percent): C, 52.5; H, 3.5;N, 4.1. Found (percent); C, 52.7; H, 3.7; N, 4.1.

EXAMPLE 36 Preparation of 3-(4-methylbenzoyl)fluoromethanesulfonanilide

A 500 ml. flask fitted with reflux condenser was charged with 10.5 g. of3-amino-4'-methylbenzophenone (0.03 mole), 6.7 g. of N,N-dimethylaniline(0.055 mole), 6.6 g. of fluoromethanesulfonyl chloride (0.05 mole) and150 ml. of methylene chloride. The reaction mixture was heated at refluxtemperature for 20 hours. Methylene chloride was then removed byevaporation, and the residue was extracted with dilute aqueous sodiumhydroxide. The alkaline extract was washed with ethyl ether, treatedwith charcoal and acidified. The precipitated solid was recrystallizedfrom ethanol-water mixtures to give analytically pure product, M.P.118-120° C.

Analysis.--Calculated for C₁₅ H₁₄ FNO₃ S (percent): C, 58.7; H, 4.6; N,4.6. Found (percent): C, 58.8; H, 4.8; N, 4.5.

EXAMPLE 37 Preparation of 3-benzoylperfluoroethanesulfonanilide

A 300 ml. Parr pressure vessel was charged with 9.85 g. of3-aminobenzophenone (0.05 mole), 150 ml. of triethylamine and 10.1 g. ofperfluoroethanesulfonyl fluoride (0.05 mole). The mixture was heated at90-100° C. for 24 hours.

Triethylamine was removed by evaporation, yielding an oil which wastaken up in benzene. The benzene solution was washed with dilutehydrochloric acid and extracted with dilute sodium hydroxide.Acidification with hydrochloric acid affords a solid which wasrecrystallized from ethanol-water to give white, solid product, M.P.95-97° C.

Analysis.--Calculated for C₁₅ H₁₀ F₅ NO₃ S (percent): C, 47.5; H, 2.7;N, 3.7. Found (percent): C, 47.7; H, 2.8; N, 3.7.

EXAMPLES 38-42

By the use of the general procedures of Examples 34-37 and thesubstitution of other haloalkanesulfonyl anhydride and halide startingmaterials, the following exemplary compounds are obtained.

    ______________________________________                                        Example No.:                                                                  ______________________________________                                        38          3-benzoylfluorochloromethanesulfonani-                                        lide.                                                             39          3-benzoyl-1,1,3-trihydroperfluoropro-                                         panesulfonanilide.                                                40          3-benzoyldichloromethanesulfonanilide.                            41          3-benzoyl-perfluoroisopropanesulfon-                                          anilide.                                                          42          3-benzoylbromomethanesulfonanilide.                               ______________________________________                                    

EXAMPLE 43 Preparation of 3-benzoyltrifluoromethanesulfoanilide

Into a 3-necked, one liter flask equipped with stirrer, condenser,addition funnel, internal thermometer and nitrogen sweep were charged59.8 g. of 3-aminobenzophenone (0.304 mole), 50.4 ml. of triethylamineand 400 ml. of chloroform. Trifluoromethanesulfonic anhydride was addedslowly to the stirred mixture at 10-25° C. (ice-bath cooling). Afterstirring at room temperature for two hours, the solution was washed withdilute hydrochloric acid and then extracted with 10 percent aqueoussodium hydroxide. The aqueous extract was washed with chloroform untilthe washes were clear, clarified with charcoal, and acidified to pH 1with concentrated hydrochloric acid. The product was collected byfiltration, washed with water and dried. Recrystallization from hexaneafforded analytically pure product, M.P. 99-101° C.

Analysis.--Calculated for C₁₄ H₁₀ F₃ NO₂ S (percent): C, 51.1; H, 3.1.Found (percent): C, 51.3; H, 3.2.

EXAMPLES 44-83

By use of the procedure of Example 43 and the substitution of otheraminobenzophenone starting materials, the following exemplary compoundswere obtained:

    __________________________________________________________________________                                  M.P., ° C.                               Ex.                           (uncor-                                         No.                           rected)                                         __________________________________________________________________________    44 2-benzoyltrifluoromethanesulfonanilide                                                                   98-100                                          45 4-benzoyltrifluoromethanesulfonanilide                                                                   136-137                                         46 3-(4-methylbenzoyl)trifluoromethanesulfonanilide                                                         129.5-131.5                                     47 3-(4-methoxybenzoyl)trifluoromethanesulfonanilide                                                        122.5-124.5                                     48 3-(4-fluorobenzoyl)trifluoromethanesulfonanilide                                                         134-136                                         49 3-(4-chlorobenzoyl)trifluoromethanesulfonanilide                                                         123.5-125.5                                     50 5-benzoyl-2-chlorotrifluoromethanesulfonanilide                                                          102-103                                         51 3-benzoyl-5-chlorotrifluoromethanesulfonanilide                                                          114-116                                         52 3-benzoyl-4-chlorotrifluoromethanesulfonanilide                                                          106-108                                         53 3-benzoyl-2-chlorotrifluoromethanesulfonanilide                                                          92-93                                           54 4-(2-chlorobenzoyl)trifluoromethanesulfonanilide                                                         144.5-146.5                                     55 4-(3-chlorobenzoyl)trifluoromethanesulfonanilide                                                         139-141                                         56 4-(4-chlorobenzoyl)trifluoromethanesulfonanilide                                                         145-147                                         57 3-benzoyl-2-methyltrifluoromethanesulfonanilide                                                          119-121                                         58 5-benzoyl-2-methyltrifluoromethanesulfonanilide                                                          84-85                                           59 3-benzoyl-5-methyltrifluoromethanesulfonanilide                                                          94-96                                           60 3-(3-methylbenzoyl)trifluoromethanesulfonanilide                                                         91-93                                           61 2-(3-methylbenzoyl)trifluoromethanesulfonanilide                                                         92-93                                           62 3-(2,5-dimethoxybenzoyl)trifluoro-                                                                       121.5-124                                          methanesulfonanilide.                                                      63 4-chloro-3-(4-methylbenzoyl)trifluoro-                                                                   88-90                                              methanesulfonanilide.                                                      64 4-chloro-3-(4-methoxybenzoyl)trifluoro-                                                                  89-90                                              methanesulfonanilide.                                                      65 4-chloro-3-(4-chlorobenzoyl)trifluoro-                                                                   82-83                                              methanesulfonanilide.                                                      66 4-chloro-3-(4-fluorobenzoyl)trifluoro-                                                                   133-134                                            methanesulfonanilide.                                                      67 3-(2-methylbenzoyl)trifluoromethanesulfonanilide                                                         92-93                                           68 4-chloro-2-(2-chlorobenzoyl)trifluoro-                                                                   86-88                                              methanesulfonanilide.                                                      69 3-(3,4-dichlorobenzoyl)trifluoro-                                                                        146-147                                            methanesulfonanilide.                                                      70 3-(2,5-dimethylbenzoyl)trifluoro-                                                                        85-86                                              methansulfonanilide.                                                       71 3-(2,3-dimethylbenzoyl)trifluoro-                                                                        107-109                                            methanesulfonanilide.                                                      72 3-benzoyl-4-methoxytrifluoromethanesulfonanilide                                                         131-132                                         73 3-(2-methoxybenzoyl)trifluoromethanesulfonanilide                                                        87-89                                           74 3-(2,6-dimethylbenzoyl)trifluoro-                                                                        113-114                                            methanesulfonanilide.                                                      75 3-(4-chloro-2-methylbenzoyl)trifluoro-                                                                   135-137                                            methanesulfonanilide.                                                      76 5-benzoyl-2-methoxytrifluoromethanesulfonanilide                                                         87-89                                           77 3-benzoyl-4-bromotrifluoromethanesulfonanilide                                                           131                                             78 3-(3,4-dimethylbenzoyl)trifluoro-                                                                        129                                                methanesulfonanilide.                                                      79 3-(2,4-dimethylbenzoyl)trifluoro-                                                                        106-108                                            methanesulfonanilide.                                                      80 3-(4-ethylbenzoyl)trifluoromethanesulfonanilide                                                          90-91                                           81 3-(3-fluorobenzoyl)trifluoromethanesulfonanilide                                                         96-98                                           82 3-benzoyl-2-methoxytrifluoromethanesulfonanilide                                                         132-133                                         83 3-benzoyl-5-methoxytrifluoromethanesulfonanilide                                                         89-91                                           __________________________________________________________________________

EXAMPLE 84 Preparation of3-benzoyl-4-hydroxytrifluoromethanesulfonanilide

Glacial acetic acid (20 ml.), 55% hydroiodic acid (7 ml.) and3-benzoyl-4-methoxytrifluoromethanesulfonanilide (1.8 g., 5 mmole) wereheated to reflux temperature and maintained at reflux for four hours.This reaction mixture was poured over ice, and the resulting mixture wasextracted with dichloromethane. The dichloromethane layer was evaporatedin vacuo to give a yellow solid. Recrystallization from benzene -cyclohexane gave light yellow3-benzoyl-4-hydroxytrifluoromethanesulfonanilide, M.P. 133-136° C.

Analysis.--Calculated for C₁₄ H₁₀ F₃ NO₄ S: (percent): C, 48.7; H, 2.9;N, 4.1. Found (percent): C, 49.1; H, 2.9; N, 4.0.

EXAMPLES 85-90

By use of the general procedure of Example 84 and the substitution ofother benzoylmethoxysulfonanilides, the following exemplary compoundswere obtained:

    __________________________________________________________________________                                  Melting                                         Ex.                           point                                           No.                           (in ° C.)                                __________________________________________________________________________    85 3-(4-hydroxybenzoyl)trifluoromethanesulfonanilide                                                        156-158                                         86 3-(3-hydroxybenzoyl)trifluoromethanesulfonanilide                                                        169-172                                         87 5-benzoyl-2-hydroxytrifluoromethanesulfonanilide                                                         178-181                                         88 3-benzoyl-5-hydroxytrifluoromethanesulfonanilide                                                         128-130                                         89 3-benzoyl-2-hydroxytrifluoromethanesulfonanilide                                                         86-88                                           90 3-(2-hydroxybenzoyl)trifluoromethanesulfonanilide                                                        131-133                                         __________________________________________________________________________

EXAMPLE 91 Preparation of N-ethyl-3-benzoyltrifluoromethanesulfonanilide

Sodium carbonate (6.89 g., 0.082 mole) was dissolved in distilled water(70 ml.) and 3-benzoyltrifluoromethanesulfonanilide (27.0 g., 0.082mole) was added in small portions. Water (30 ml.) was added and thesolution as stirred for three hours. The solution was filtered and thefiltrate was evaporated to dryness in vacuo. The solid was dissolved inethanol, treated with decolorizing charcoal and filtered. The filtratewas evaporated to dryness in vacuo, and the solid sodium3-benzotrifluoromethanesulfonanilide was dried.

Analysis.--Calculated for C₁₄ H₉ F₃ NNaO₃ S (percent): C, 48.0; H, 2.16.Found (percent): C, 48.0; H, 2.8.

Sodium 3-benzoyltrifluoromethanesulfonanilide (20 g., 57 mmole), acetone(250 ml.) and ethyl iodide (11.7 g., 75 mmole) were heated to reflux andmaintained at reflux temperature for 1 day. The reaction mixture wasevaporated to remove solvent and the oil obtained was dissolved inchloroform. The solution was washed twice with 10 percent sodiumhydroxide, twice with water and dried over magnesium sulfate; thentreated with decolorizing charcoal and filtered. The solvent was removedin vacuo and the liquid product was distilled through a molecular stillto give a light yellow liquid,N-ethyl-3-benzoyltrifluoromethanesulfonanilide, column temperature 170°C., pressure 1 × 10⁻ ⁵ mm. of mercury.

Analysis.--Calculated for C₁₆ H₁₄ F₃ NO₃ S (percent): C, 53.8; H, 3.95.Found (percent): C, 53.8; H, 4.0.

EXAMPLES 92-101

By the use of the general procedure of Example 91 and the substitutionof other reactive alkyl halides or dialkyl sulfates the followingexemplary compounds are obtained:

    ______________________________________                                        Example No.:                                                                  ______________________________________                                        92         N-methyl-3-benzoyltrifluoromethanesul-                                        fonanilide.                                                        93         N-n-propyl-3-benzoyltrifluoromethanesul-                                      fonanilide.                                                        94         N-allyl-3-benzoyltrifluoromethanesulfon-                                      anilide.                                                           95         N-methyl-3-benzoyldifluoromethanesul-                                         fonanilide.                                                        96         N-methyl-3-benzoyl-4-hydroxytrifluoro-                                        methanesulfonanilide.                                              97         N-methyl-3-benzoylfluorochloromethane-                                        sulfonanilide.                                                     98         N-methyl-3-(4-chlorobenzoyl)trifluorometh-                                    anesulfonanilide.                                                  99         N-methyl-3-benzoyl-4-methoxytrifluoro-                                        methanesulfonanilide.                                               100       N-methyl-3-benzoylchloromethanesulfon-                                        anilide.                                                            101       N-ethyl-3-benzoylchloromethanesulfonani-                                      lide.                                                              ______________________________________                                    

Additional compounds of the invention prepared by the foregoing generalprocedures are as follows:

    __________________________________________________________________________                                   Melting                                        Ex.                            point                                          No.                            (in ° C.)                               __________________________________________________________________________    102 3-(3-trifluoromethylbenzoyl) trifluoromethanesul-                                                        86-88                                              fonanilide.                                                               103 3-(2-trifluoromethylbenzoyl)trifluoromethanesul-                                                         110-111                                            fonanilide.                                                               104 3-(4-trifluoromethoxybenzoyl)trifluoromethanesul-                                                        107-109                                            fonanilide.                                                               __________________________________________________________________________

What is claimed is: .[.1. A compound of the formula: ##SPC5## whereinR_(x) is a haloalkyl group having up to four carbon atoms and at leastone halogen atom bonded to the alpha carbon atom or if there is nohalogen bonded to said alpha carbon atom, having at least 2 halogenatoms bonded to the beta carbon atom, R is hydrogen, alkyl or alkenylcontaining not more than three carbon atoms, or a pharmaceuticallyacceptable cation; each Y is selected from hydroxy, halogen and alkyl,alkoxy, haloalkyl and haloalkoxy groups having up to 4 carbon atoms andn and n' are each 0-3..]. .[.2. A compound according to claim 1 whereinthe halogen atoms in the R_(x) group are all fluorine..]. .[.3. Acompound according to claim 2 wherein R_(x) is a perfluoroalkylgroup..]. .[.4. N-methyl 3-benzoyltrifluoromethanesulfonanilideaccording to claim 3..]. .[.5.3-benzoyl-4-hydroxytrifluoromethanesulfonanilide according to claim3..]. .[.6. A compound according to claim 1, in which thehaloalkanesulfonamido group is in meta orientation to the carbonylgroup..]. .[.7. A compound according to claim 6, in which R_(x) is HCF₂--..]. .[.8. 3-benzoyldifluoromethanesulfonanilide according to claim7..]. .[.9. The sodium salt of 3-benzoyldifluoromethanesulfonanilideaccording to claim 7..]. .[.10. A compound according to claim 6, inwhich R_(x) is H₂ CF--..]. .[.11. 3-benzoylfluoromethanesulfonanilideaccording to claim 10..]. .[.12. A compound of the formula: ##SPC6##wherein R_(x) is a haloalkyl group having up to two carbon atoms and atleast one halogen atom bonded to the alpha carbon atom or if there is nohalogen bonded to said alpha carbon atom, having at least two halogenatoms bonded to the beta carbon atom, provided that the halogen in R_(x)is selected from chlorine and fluorine; R is hydrogen, methyl, ethyl ora pharmaceutically acceptable cation; each Y is selected from hydroxy,halogen, methyl and methoxy; and n and n' are each 0-1..]. .[.13. Acompound according to claim 12 of the formula: ##SPC7##.]. .[.14. Acompound according to claim 2 wherein R_(x) is trifluoromethyl..]..Iadd.
 15. A compound of the formula ##SPC8## wherein R_(x) is afluoromethyl group, R is hydrogen, alkyl or alkenyl containing not morethan three carbon atoms, or a pharmaceutically acceptable cation; each Yand Y' is selected from hydroxy, halogen and alkyl, alkoxy, haloalkyland haloalkoxy groups having up to 4 carbon atoms and n and n' are each0-3. .Iaddend..Iadd.
 16. A compound according to claim 15 wherein R_(x)is CF₃ --. .Iaddend. .Iadd.
 17. N-methyl3-benzoyltrifluoromethanesulfonanilide according to claim 16..Iaddend..Iadd.
 18. 3-Benzoyl-4-hydroxytrifluoromethanesulfonanilideaccording to claim
 16. .Iaddend..Iadd.
 19. A compound according to claim15 in which R_(x) is HCF₂ --. .Iaddend..Iadd. 20.3-Benzoyldifluoromethanesulfonanilide according to claim 19..Iaddend..Iadd.
 21. The sodium salt of3-benzoyldifluoromethanesulfonanilide according to claim 19..Iaddend..Iadd.
 22. A compound according to claim 15 in which R_(x) isH₂ CF--. .Iaddend..Iadd.
 23. 3-Benzoylfluoromethanesulfonanilideaccording to claim
 22. .Iaddend..Iadd.
 24. A compound according to claim15 of the formula: ##SPC9## wherein R is hydrogen, methyl, ethyl or apharmaceutically acceptable cation. .Iaddend.